Metals can produce varied effects on biochemical processes and it now seems clear that induction of (metal-binding) proteins should be included among the diversity of responses multivalent metal ions elicit in biochemical systems. The induction of a great many proteins has been studied, yet the mechanisms by which this phenomenon is produced in mammalian systems remains obscure. The proposed study is designed to further elucidate the induction process initated by cadmium, copper, and mercury, known to bind to metallothionein, and to characterize the proteins induced in response to high levels of the respective metals. Both whole animal and isolated single cell in vitro studies will be utilized to gain insight into the role metals play in the inductive process. Among the specific questions to be addressed are the following: what conditions prevent the cell from responding in a regulated manner to a given signal from the effector (the metal)? What is the precise "threshold" of metal toxicity to liver cells? Do male and female liver cells differ in their capacity for metal-binding protein synthesis? In addition, the mechanism of induction will be explored by analyzing and characterizing chromosomal materials. Hopefully, the study should give insight into molecular events which determine biological tolerance, as opposed to toxicity, and should contribute to our understanding of the regulation of specific gene expression.